Most breast tumors contain estrogen receptors (ER) that regulate tumor cell growth and mediate the action of estrogen antagonists such as tamoxifen. Not all breast cancers, however, respond to hormone therapy. Therefore, it is important to have effective prognostic tools that will identify those patients most likely to be hormone responders, so that they can be treated with this well tolerated therapy, whereas those unlikely to respond can promptly begin regimens of radiation of chemotherapy. The presence of ER in most breast tumors provides a mechanism for selective localization of estrogens, which if labeled with suitable radionuclides, could be used for diagnostic imaging or radiotherapy or breast tumors. During past periods of support on this project, we have developed a series of estrogens labeled with fluorine-18 and carbon-11, some of which are effective agents of imaging estrogen receptor positive (ER+) tumors. Other investigators have developed other adiohalogenated estrogens for ER-mediated radiotherapy. Other investigators have developed other radiohalogenated estrogens for ER-mediated radiotherapy. Also, recent investigations have revealed that another estrogen receptor subtype, ERbeta, is present in some target tissues, including breast tissue and tumors. We have three goals of the next phase of this project: (1) We intend to develop ER ligands for breast tumor imaging that are labeled with the readily available radionuclide, technetium-99m, as well as its rhenium congener. To accomplish this, we will investigate novel aspects of technetium organometallic chemistry through the application of three new methods for the preparation of cyclopentadienyl tricarbonyl technetium and related systems. These functionalities will be incorporated are pendant and integral groups into steroidal and non-steroidal ER ligands. (2) Based on emerging differences in the structure-binding affinity relationships for ERalpha and ERbeta ligands, derived in part from our investigations, we will prepare ligands selective for these receptors and develop them as tumor imaging agents. (3) We will utilize several radionuclides (iodine-123, and 124 and bromine-76, 77, the later three available to use through a collaboration to prepare ER ligands for radiotherapy,, and we will have these tested in appropriate animal tumor model systems. These investigations should lead to substantial advances in the availability of diagnostic imaging gents for ER+ tumors and ER subtype- selective imaging agents, to the evaluation in vivo of radiotherapeutic ER ligands.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA025836-27
Application #
7007322
Study Section
Special Emphasis Panel (ZRG7-DMG (04))
Program Officer
Menkens, Anne E
Project Start
1984-01-01
Project End
2007-06-30
Budget Start
2006-01-01
Budget End
2007-06-30
Support Year
27
Fiscal Year
2006
Total Cost
$350,199
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Zhou, Dong; Xu, Jinbin; Mpoy, Cedric et al. (2018) Preliminary evaluation of a novel 18F-labeled PARP-1 ligand for PET imaging of PARP-1 expression in prostate cancer. Nucl Med Biol 66:26-31
Zhou, Dong; Kim, Sung Hoon; Chu, Wenhua et al. (2017) Evaluation of aromatic radiobromination by nucleophilic substitution using diaryliodonium salt precursors. J Labelled Comp Radiopharm 60:450-456
Min, Jian; Guillen, Valeria Sanabria; Sharma, Abhishek et al. (2017) Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells. J Med Chem 60:6321-6336
Fowler, Amy M; Clark, Amy S; Katzenellenbogen, John A et al. (2016) Imaging Diagnostic and Therapeutic Targets: Steroid Receptors in Breast Cancer. J Nucl Med 57 Suppl 1:75S-80S
Zhou, Dong; Chu, Wenhua; Peng, Xin et al. (2015) Facile purification and click labeling with 2-[(18)F]fluoroethyl azide using solid phase extraction cartridges. Tetrahedron Lett 56:952-954
Zhou, Dong; Lin, Mai; Yasui, Norio et al. (2014) Optimization of the preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16beta-[18F]fluoro-5alpha-dihydrotestosterone (FDHT) as radiopharmaceuticals. J Labelled Comp Radiopharm 57:371-7
Dehdashti, Farrokh; Laforest, Richard; Gao, Feng et al. (2012) Assessment of progesterone receptors in breast carcinoma by PET with 21-18F-fluoro-16?,17?-[(R)-(1'-?-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione. J Nucl Med 53:363-70
Ackroyd, Nathan C; Katzenellenbogen, John A (2010) Pyridyl-Cyclopentadiene Re(CO)(2) Complexes as a Compact Core Systems for SPECT Ligand Development. Organometallics 29:3669-3671
Lee, Byung Chul; Dence, Carmen S; Zhou, Haibing et al. (2009) Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-gamma ligands: potential positron emission tomography imaging agents. Nucl Med Biol 36:147-53
LaFrate, Andrew L; Katzenellenbogen, John A (2007) Improved chemical syntheses of 5,6-dihydro-5-fluorouracil. J Org Chem 72:8573-6

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